SK&F 101926, a synthetic
peptide, is a potent antagonist of
vasopressin at both the V2 and the
V1 receptors. Following
intravenous administration of
SK&F 101926 (5 mg/kg), mean arterial pressure (MAP) immediately fell 75 mm Hg. Heart rate increased approximately 50 beats/min. Cutaneous
flushing and
cyanosis appeared approximately 2 to 5 min after the
SK&F 101926 administration. Three of the five rats died within 40 min with no improvement in either color or MAP. The two surviving animals slowly recovered from these symptoms. The
hypotension and
flushing recorded in these studies resembled the effects during hypotensive
shock.
SK&F 101926 degranulated rat peritoneal mast cells in vitro as measured by the liberation of
histamine. Analogs of
SK&F 101926 were identified having reduced activity to release
histamine from mast cells in vitro. The activity of these analogs to release
histamine in vivo was also tested, as reflected by rat paw
edema. A positive correlation was found between the potency to produce
edema in vivo and the potency to release mast cell
histamine in vitro (r = 0.94, p less than 0.05). In addition, compounds that released mast cell
histamine and induced rat paw
edema also produced
hypotension and death when administered intravenously, while analogs which produced minimal histamine release in vitro produced minimal or no cardiovascular changes or lethality in vivo at the same dosages (5 mg/kg). Finally,
cyproheptadine (10 mg/kg), an antagonist at both the
serotonin and the
histamine receptors, blunted the effects of
SK&F 101926 on MAP and blocked the lethality. Pretreatment with a combination of
histamine (H1 and H2) antagonists provided little protection against the SK&F 101926-induced toxicity. These data indicate that the cardiovascular toxicity of
SK&F 101926 (and related
peptides) is mediated via the release of autocoids from mast cells.
Serotonin appears to play a major role in mediating the cardiovascular toxicity of
SK&F 101926.